For pediatric administration of supplements and pharmaceuticals it is well recognized by those of skill in the art that solutions or liquid suspensions are highly preferable dosage forms. Tablets and capsules are difficult for children to swallow and the amount of drug delivered is not as flexible as is often required for pediatric drugs. With liquid dosage forms, by contrast, the amount of drug delivered to the patient can be varied over a wide range merely by regulating the volume of dose of known concentrations.
From the perspectives of ease of use, accuracy of dose, and bioavailability, oral liquid dosage forms are generally preferred to be in the form of a solution. From the perspective of taste, oral liquid dosage forms are generally preferred to be in the form of a suspension which tends to mask the taste of the drug. This is essentially useful with pediatric treatments as children generally do not like the taste of medicines. If the taste is not pleasing, the child can spit it out and therefore affect the treatment regimen. Especially for pediatric use, where doses are relatively small, accuracy and precision of dose is extremely important. For this reason, the preferable oral liquid form for many antibiotics for children is an oral suspension.
Amoxicillin is well known as a treatment for various bacterial infections and its use as an antibiotic, alone or in combination with other compositions and medications has been documented. However, treatment of certain bacterial infections has been made more difficult by resistance. In particular, many gram negative bacteria produce an enzyme, β-lactamase, that attacks the β-lactam ring of β-lactam antibiotics and renders them ineffective. To counteract this effect, β-lactamase inhibitors have been developed that can bind to β-lactamase and prevent it from attacking the antibiotic. The antibiotic and the inhibitor are preferably administered together. For example the β-lactam antibiotic amoxicillin can be administered with the β-lactamase inhibitor clavulanate potassium. This additional clavulanate potassium is not needed in non-beta lactamase mediated resistance treatments.
Moreover, the amount of amoxicillin has increased in dosage as certain bacteria have become resistant to the amoxicillin. For instance, Streptococcus pneumoniae have become resistant to amoxicillin such that the prescribed treatment dosage has increased from 400 mg/5 mL per day to over 600 mg/5 mL per day over the last decade. The amount of the clavulanate potassium has similarly increased or remained constant and in ratio with the increased amount of amoxicillin per dosage. Further the actual combined taken dosage for the patient, of the combined amoxicillin and clavulanate potassium has in fact doubled over the last few years, such as taking the dosage 2 or 3 times per day during treatment.
A combination of amoxicillin and clavulanate potassium is a treatment of choice for acute otitis media. Symptoms of acute otitis media include fever, otalgia, irritability and/or pain, fussiness, tugging or rubbing or holding of the ears, sleeping and feeding disturbances, and infrequently, perforation of the tympanic membrane. Most of these symptoms are mild to moderate and will eventually resolve spontaneously. The combination of amoxicillin and clavulanate potassium is considered the gold standard for antibiotic treatment, against which most new products on the market are compared. Resistant otitis media is on the rise in the pediatric population, it is believed, due to resistant organisms.
Acute otitis media remains the most frequently occurring infection for which antimicrobial agents are prescribed for children in the United States. Concerns about the development of antimicrobial resistance have led to recommendations to withhold antibiotics from such children unless symptoms persist or worsen, which is sometimes referred to as a “watchful waiting strategy”, which can prolong the acute otitis media symptoms for the child.
Notably, due to vaccination there has been a selective reduction of treatable S. pneumoniae compared to resistant Haemophilus influenzae as causative agents. The resistance building up to amoxicillin has led to the increase of the dosage and/or dosage unit of amoxicillin in certain antibiotic compositions. Correspondingly, the other active pharmaceutical ingredients in such antibiotic compositions has also increased, typically based on ratios. Further, in addition to H. influenzae, another beta-lactamase bacteria of Moraxella catarrhalis is also seen in otitis media, although to a much lesser extent than H. influenzae. 
Formulations of amoxicillin-clavulanate potassium have used varying ratios of the two components; over time, the trend has been to increase the dosage of amoxicillin, mainly to achieve higher efficacy rates against S. pneumoniae. Amoxicillin-clavulanate potassium ratios have thus ranged from 4:1 to 14:1. The currently available commercial amoxicillin-clavulanate potassium suspension for pediatric use contains 600 mg of amoxicillin and 42.9 mg of clavulanate potassium per 5 mL (a ratio of 14:1). The currently recommended pediatric dosage, 90/6.4 mg/kg/day administered in two divided doses for 10 days, results in a dose of clavulanate potassium almost twice as high as the dose recommended for adults (6.4 mg/kg/day vs. 3.5 mg/kg/day). The currently recommended adult dosage ranges from 500 mg/250 mg-4,000 mg/250 mg per day with a common dose being 1700 mg/250 mg per day.
Certain current formulations of amoxicillin and clavulanate potassium have a high concentration of clavulanate potassium. However clavulanate potassium has the potential to cause rare serious side effects such as jaundice and hepatitis (see, for example, Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004). Other minor systemic reactions include headache, rash, mycosis, vaginitis, and agitation. The following infrequent and rare adverse reactions have been reported for ampicillin-class antibiotics: hepatitis; cholestatic jaundice; hemorrhagic/pseudomembranous colitis; angioedema; Stevens-Johnson syndrome; hypersensitivity vasculitis; tooth discoloration; and seizure.
More frequently, in pediatric patients clavulanate potassium may cause diarrhea (Reed, M. D. (1998) Clinical pharmacokinetics of amoxicillin and clavulanate potassium. Pediatric Infectious Disease Journal 17, 957-62), which can lead to dehydration in such young patients and further sickness. Although advantageous from the standpoint of efficacy, use of amoxicillin and clavulanate potassium is also associated with a relatively high incidence of diarrhea. This diarrhea is infrequently severe enough to require discontinuing treatment, but it may occasion delays in children's returning to day care and in parents' returning to work. While not being bound by theory, it is possible that the occurrence of diarrhea is related to the clavulanate potassium component of the drug combination.
Clavulanate potassium may also cause vomiting and diaper rash in children. These more common side effects of diarrhea, diaper rash, vomiting and oral moniliasis, while not as serious as the other side effects, are debilitating to the care givers of the pediatric patient. The pediatric patient with diarrhea and/or vomiting cannot return to school or day care until typically twenty-four (24) hours after the last episode of diarrhea or vomiting. Such constraints affect the parents and care giver of the pediatric patient in that they typically must use vacation days to stay home with the vomiting child, or work from home with a reduced productive outcome. Given the data that approximately twenty percent (20%) of all pediatric patients taking the current dosage of amoxicillin and clavulanate potassium experience some diarrhea and/or vomiting, this translates to twenty percent (20%) of children not able to return to school or day care and consequently twenty percent (20%) of parents or care givers staying home with the affected pediatric patient. It is thus discovered and sought to minimize the amount of clavulanate potassium necessary for treatment of children to be very useful.
While not wishing to be bound by theory, it is possible that clavulanate potassium has the property of binding irreversibly to β-lactamase. (Reed, M. D. (1998). Clinical pharmacokinetics of amoxicillin and clavulanate potassium. Pediatric Infectious Disease Journal 17, 957-62), thus enhancing the effectiveness of amoxicillin. If so, then this might explain the rapidly declining need for clavulanate potassium in the course of a combined treatment with amoxicillin and clavulanate potassium. After an initial loading dose of clavulanate potassium is provided, either the same amount or much less may be needed. Continuing to administer the same composition of amoxicillin and clavulanate potassium over the treatment regimen period, as the currently prescribed method, may result in too much clavulanate potassium being taken in subsequent doses.
Clearly for a pediatric population it is particularly important to use the minimal, yet effective, amount of clavulanate potassium so as to reduce the risk of diarrhea, diaper dermatitis and vomiting in a young population. We have discovered that overall less clavulanate potassium is required for the entire treatment regimen, which can either be (a) a lower dose through the regimen, (b) high dose of clavulanate potassium at the beginning of treatment to bind to β-lactamase and then less throughout the regimen, or (c) a combination thereof and varying dosages throughout the treatment regimen. Thus, either the same smaller amount, or less, clavulanate potassium may be required as treatment progresses. However in current treatments amoxicillin and clavulanate potassium are administered in a set combined dosage form administered at the same level at a ratio of about 4:1-14:1 over a period of days (typically ten (10) days). Although various amoxicillin and clavulanate potassium regimens are available, the need for minimizing clavulanate potassium has not been adequately addressed. Until recently, the thrust behind reformulations of amoxicillin-clavulanate potassium has been adequate coverage of S. pneumoniae. Currently, focus has shifted to adequate coverage of H. influenzae. However, minimizing adverse events and side effects has not been given precedence over the efficacy of the dosage formulation to address S. pneumoniae, H. influenzae and other causes of infections.
For instance, in a study published in the New England Journal of Medicine in January 2011, the table below (Table 1) shows the higher rates of diarrhea, vomiting and diaper dermatitis in children taking amoxicillin-clavulanate potassium versus those taking a placebo.
TABLE 3Complications and Adverse Events According to Study Group and Treatment Received at the Time of Occurrence.*Amoxicillin-Clavulanate Group (N = 144)During Receipt ofPlacebo Group (N = 147)Amoxicillin-During Receipt ofDuring Receipt ofDuring Receipt ofClavulanateRescue TherapyTotalPlaceboRescue TherapyTotalAdverse Eventnumber of children (percent)Mastoiditis†0001 (1)01 (1)Perforation of tympanic membrane1 (1)01 (1)6 (4)1 (1)7 (5)Protocol-defined diarrhea‡34 (24)2 (1)36 (25)11 (7) 11 (7)  22 (15)§Diaper-area dermatitis67 (47)6 (4)73 (51)24 (16)27 (18) 51 (35)¶Oral thrush7 (5)07 (5)01 (1)1 (1)Vomiting∥12 (8) 012 (8) 11 (7) 1 (1)12 (8) Rash**1 (1)01 (1)1 (1)1 (1)2 (1)*In each study group, one child was not followed beyond enrollment. Comparisons were adjusted for study site, history or no history of recurrent acute otitis media, and exposure or no exposure to other children.†Mastoiditis developed on day 5 in an 11-month-old child with unilateral acute otitis media and a score on the Acute Otitis Media Severity of Symptoms (AOM-SOS) scale of 14 at entry and of 7 on day 5. A culture of middle-ear aspirate yielded serotype 19A Streptococcus pneumoniae with a penicillin minimum inhibitory concentration of 2 μg per milliliter. The child was hospitalized for 41 hours and treated initially with parenteral antibiotics and subsequently with oral antibiotics; he recovered uneventfully.‡Diarrhea was defined in the protocol as three or more watery stools in 1 day or two watery stools daily for at least 2 days. Treatment was discontinued because of diarrhea in six children in the amoxicillin-clavulanate group and one child in the placebo group, in whom Clostridium difficile enteritis developed.§P = 0.05 for the difference between the amoxicillin-clavulanate group and the placebo group.¶P = 0.008 for the difference between the amoxicillin-clavulanate group and the placebo group.∥In the amoxicillin-clavulanate group, treatment was discontinued in one child because of vomiting.**In each group, treatment was discontinued in one child because or rash.
Thus, a need exists for an amoxicillin-clavulanate potassium composition, and treatment method, which reduces the side effects of diarrhea, vomiting and diaper dermatitis in children, while still maintaining the high efficacy of the antibiotic combination. One of the objectives of the invention is to maintain high efficacy while improving safety profile, namely reducing the common and disruptive side effects of diarrhea, vomiting and diaper dermatitis in pediatric patients.
Various formulations and dosing modalities currently exist for the combination of amoxicillin-clavulanate potassium. Tablets and suspensions are also available. Delayed release tablet formulations have been developed (see for example U.S. Pat. Nos. 5,910,322; 6,299,903; 6,544,558; 6,756,057; 6,783,773; 6,977,086; 7,122,204; 7,534,781; and publications 2006/0121106, 2008/0300569, and 2011/0020408).
However, these systems provide combination doses of amoxicillin-clavulanate potassium that do not address the need for a reduced set amount of clavulanate potassium (whether constant throughout the treatment or in a reduced set amount when compared to current conventional and known amounts) throughout the treatment regimen, including reducing the amount as treatment progresses. There is a need for a dosage, and a method that provides a means of reducing the overall amount of clavulanate potassium for the treatment regimen, when compared to current conventional and known dosage amounts and methods of treatment.
Thus, a need exists for a pediatric oral suspension composition having amoxicillin-clavulanate potassium to maintain the efficacy of the composition in view of beta-lactamase mediated resistance H. influenzae and M. catarrhalis, without elevating the possibility of the severe side affects of jaundice and hepatitis and the more common and disruptive side effects of diarrhea, diaper rash and vomiting.
These and other needs are met by the present invention including a composition and a method for treating bacterial infections, including acute otitis media and other respiratory infections such as but not limited to acute bacterial rhinosinusitis. Other advantages of the present invention will become apparent from the following description and appended claims.